What are Regulatory Submissions?
Last updated on: September, 2024
Regulatory submissions consist of comprehensive information and data requested by Regulatory agencies to evaluate the safety and efficacy of a healthcare product for clinical testing or marketing approval.
Over the years, the Electronic Common Technical Document (eCTD) has become the standard format for Regulatory submissions to numerous global health authorities. It is mandatory for a wide range of submissions, spanning from investigational applications to marketing authorizations, and encompasses all documentation related to lifecycle management, such as amendments, supplements, and annual reports. The International Council for Harmonisation (ICH) has established eCTD formatting requirements that apply to various health authorities worldwide, including the FDA's Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER), the European Medicines Agency (EMA), the Medicines and Healthcare products Regulatory Agency (MHRA), Swiss Medic, the Therapeutic Goods Administration (TGA), and Health Canada.
Navigating eCTD publishing can be intricate and costly, particularly as Regulatory agencies increasingly mandate electronic submission formats for various types of submissions. These include eCTD submissions supporting New Drug Applications (NDAs), Marketing Authorisation Applications (MAAs), New Drug Submissions (NDS), Investigational New Drug (IND) applications, among others. Furthermore, maintaining compliance will pose growing challenges as Regulatory requirements and directives evolve across different markets.
Freyr offers services aimed at mitigating common issues that often result in submission rejections. By collaborating with a team of experts with a proven track record in Regulatory submissions, compliance, and eCTD management software, Freyr provides comprehensive support to ensure successful Regulatory outcomes. Adhering to Regulatory standards and adjusting to policy shifts enable companies to introduce safe and efficient products to the market, effectively maneuvering through intricate Regulatory environments.
Framework for the ICH eCTD v4.0
Since ICH's inception in 1990, the ICH process has gradually evolved. Beside the development of Tripartite ICH Guidelines on Safety, Quality and Efficacy topics, work was also undertaken on a number of important multidisciplinary topics, like MedDRA (Medical Dictionary for Regulatory Activities; ICH topic M1) or the CTD (Common Technical Document, ICH topic M4). Starting in the new millennium, the need to expand communication and dissemination of information on ICH Guidelines with non-ICH regions became a key focus, accompanied by the need to facilitate the implementation of ICH Guidelines in ICH's own regions.
In the last 10 to 15 years, more and more attention was given to the maintenance of already existing Guidelines as science and technology continued to evolve. The need to leverage with other organisations was also acknowledged, particularly for the development of electronic standards. ICH recognised the benefits afforded by collaboration with international standards development organisations, from the perspective of a larger pool of technical expertise and the promising opportunity to progress ICH standards as global standards. This would also allow for extending the benefits of harmonisation beyond the ICH regions by increasing participation of non-ICH regions in guideline development.
The most desirable long-term objective is to have one globally used electronic message standard to exchange information on regulated products based on internationally approved and interoperable standards.
In 2006 a basic process description for the involvement of and collaboration with other Standard Development Organisations (SDOs), initially International Organization for Standardization (ISO), HL7 and European Committee for Standardization (CEN), was drafted based on the "List of Critical Conditions for the SDO Message Standard Development Process". During the same meeting, the ICH Steering Committee (SC) approved to progress the E2B (R) and M5 messages development with the SDO consortium to evaluate the SDO process.
At the ICH meeting in October 2007 in Yokohama, a decision was made to move to the next major version of eCTD specification in collaboration with SDOs instead of making slight revisions to the eCTD Page 5 specification to a next minor version 3.3.3. During the ICH meeting in June 2008 in Portland, the Steering Committee endorsed that ICH would approach HL7 to discuss options to progress the eCTD Next Major Version through the Joint Initiative, a collaboration of ISO, CEN and HL7. To evaluate the acceptability of the resulting standard, ICH collected and collated requirements from each region into a draft ICH requirements document. An ICH Expert Working Group (EWG) and Implementation Working Group (IWG) was established to focus on the next major version of eCTD during the meeting in Fukuoka in November 2010, and the new ICH EWG/IWG M8 met for the first time as a group in June 2011 in Cincinnati.
M8 presented the concept to develop the eCTD Version 4.0 until Step 2 of the ICH process while also working through the HL7 standards development process to enhance the existing RPS Release 1 Standard. At this time point, the enhanced HL7 RPS Standard would be submitted into an ISO fast track process with the result to become an international adopted ISO Standard. In parallel ICH M8 would continue the ICH process with the development of concepts, specifications, guidance and a set of tests to support the implementation of the expected ISO standard. This was planned as Step 3 and 4 activities of the ICH process to be in alignment with the publication of the ISO standard based on the HL7 Version 3 RPS Release 2 Normative Standard, and the ICH eCTD v4.0 Implementation Guide.
In 2015 ICH M8 published the Step 2 ICH eCTD v4.0 Implementation Guide for public consultation and the updates to this document are a result of those public comments. In September 2015 HL7 published the RPS Release 2 Normative Standard. Due to changes in the HL7 and ISO processes RPS Release 2 is not currently an ISO standard. The decision to publish this Step 4 implementation guide will allow regions to move forward with implementation and the acceptance of eCTD v4.0 submissions with the understanding that some regions will not be able to mandate eCTD v4.0 until there is an approved ISO RPS standard.
What are the potential benefits of eCTD 4.0 Standard?
Recognizing the limitations of the current version, eCTD 4.0 offers several benefits:
- It accommodates all product types
- It provides a singular format for all agencies/regions/centers
- It allows for reduced structural changes and software release cycles
- It facilitates a harmonized submission unit, containing all content from Module 1 through Module 5 in one exchange message
- It enables easy correction of metadata/keyword definitions and structure without resubmitting physical files
- It allows for advanced lifecycle management and document granularity adjustments while maintaining relationships
- It supports document reuse across Regulatory activities and applications through unique identifiers
- It utilizes controlled vocabularies for easier updates to allowed values without system or tool updates
- It ensures consistent grouping of documents within sections across ICH regions using group titles
Regulated markets and semi-regulated markets accepting submissions in paper/NEES/eCTD format
United States (US) - Food and Drug Administration (FDA)
Submission Formats: FDA accepts submissions in various formats, including paper, electronic (eCTD), and hybrid formats (combination of paper and electronic).
While eCTD is not mandatory for all submissions, The FDA requires eCTD format for all New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), and Biologics License Applications (BLAs). Paper Submissions are only accepted in exceptional circumstances with prior approval.
European Union (EU) - European Medicines Agency (EMA)
Submission Formats: EMA mandates submissions in eCTD format for centralized procedures. For decentralized and mutual recognition procedures, eCTD is also recommended.
eCTD is mandatory for all applications submitted to EMA, including marketing authorization applications and variations.
Canada - Health Canada:
Health Canada regulates pharmaceuticals, biologics, medical devices, and natural health products. The use of eCTD helps improve the efficiency of the Regulatory review process and facilitates electronic submissions.
Submission Formats: Health Canada accepts submissions in both paper and eCTD formats. For certain submissions, such as New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs), eCTD is mandatory.
Japan - Pharmaceuticals and Medical Devices Agency (PMDA):
PMDA regulates pharmaceuticals, medical devices, and regenerative medicine products. Submission Formats: PMDA accepts submissions in paper and electronic formats, including eCTD.
While eCTD is recommended, it is not mandatory. However, eCTD is becoming increasingly preferred by PMDA for its efficiency and standardization.
China - National Medical Products Administration (NMPA):
NMPA regulates pharmaceuticals, medical devices, cosmetics, and food products.
Submission Formats: NMPA accepts submissions in paper and electronic formats, but electronic submissions are encouraged.
As of now, eCTD is not mandatory but is increasingly preferred by NMPA for its efficiency and standardization.
Australia - Therapeutic Goods Administration (TGA):
TGA regulates pharmaceuticals, medical devices, and complementary medicines.
Submission Formats: TGA accepts submissions in both paper and eCTD formats.
eCTD is recommended but not mandatory for most submissions. However, it is mandatory for certain submissions, such as new chemical entities.
Brazil - Agência Nacional de Vigilância Sanitária (ANVISA):
ANVISA regulates pharmaceuticals, medical devices, cosmetics, and food products.
Submission Formats: ANVISA accepts submissions in paper and electronic formats.
eCTD is not mandatory but is accepted for certain applications, such as clinical trial submissions.
India - Central Drugs Standard Control Organization (CDSCO):
CDSCO regulates pharmaceuticals and medical devices in India.
Submission Formats: CDSCO accepts submissions in paper and electronic formats.
eCTD is not mandatory but is accepted for certain applications, such as new drug approvals.
While some markets have mandated the use of eCTD for Regulatory submissions, others accept it as a recommended format. However, the trend is moving towards greater acceptance and use of eCTD due to its advantages in streamlining the Regulatory submission process and improving efficiency.
Regulatory submission process
A structured approach to eCTD publishing and submission ensures to tackle even the most demanding Regulatory requirements and hence the right approach is much needed.
Step 1: Planning and Preparation is Key
- Start Early: Don't wait until the last minute. Begin planning well in advance to ensure ample time for content creation, review, and quality checks.
- Assemble Your Team: Gather a cross-functional team with service expertise in Regulatory affairs, document management, and quality assurance. Define roles and responsibilities clearly.
- Identify Requirements: Thoroughly research the specific eCTD requirements for your target market and application type. Consider regional variations and upcoming Regulatory changes.
- Content Management: Establish a robust system for content creation, version control, and document lifecycle management. Leverage dedicated eCTD publishing software for efficiency and accuracy.
The Critical role of the Regulatory submission experts
The Regulatory Affairs (RA) professional occupies a central and indispensable position within the pharmaceutical and healthcare sectors. These specialists are entrusted with the pivotal task of preparing and submitting a diverse range of Regulatory documents, ensuring adherence to stringent guidelines and regulations mandated by Regulatory bodies. Throughout the entirety of the clinical development process, RA specialists shoulder the ultimate responsibility for the maintenance of Investigational New Drug Applications (INDs) and New Drug Applications (NDAs), thereby facilitating the seamless continuation of drug research in the United States.
On a daily basis, RA specialists engage in cross-functional collaboration with a multitude of departments, including manufacturing, medical, clinical, non-clinical, and marketing divisions. This collaborative effort is essential for assimilating the multifarious reports and findings from diverse areas into comprehensive Regulatory submissions. Consequently, individuals in Regulatory roles gain invaluable insights and maintain a uniquely broad perspective on the operational dynamics within their respective companies.
Regional eCTD submission requirements
The International Council for Harmonisation (ICH) provides the foundation for eCTD structure and content (Modules 2-5). This ensures data consistency across regions. But remember, regional variations exist, primarily in:
- Module 1: This regional chameleon houses country-specific requirements, like prescribing information, packaging details, and local forms (think PDUFA fees in the US).
- Validation Criteria: Each region establishes its own standards for eCTD validation, ensuring your file formats, metadata, and cross-references meet their specific requirements.
Freyr's approach to eCTD 4.0 submissions
Across the globe, Regulatory bodies are gearing up to adopt recent developments like eCTD v4.0 for dossier submissions, amendments, and other reports. eCTD v4.0 is an incremental change likely to impact the future of Regulatory submissions, with every country gearing up to accept and implement it. eCTD v4.0 is sure to revolutionize electronic submissions. We at Freyr are at the forefront of driving innovation through technology and are geared to support our customers by making our Regulatory submission and publishing software - Freyr SUBMIT PRO eCTD v4.0 ready. The industry will finally begin to benefit from some much-needed changes to the Regulatory submission process that will lead to faster approval times and speedy access to new products for patients. The COVID-19 pandemic recently did show us the value and need for faster medication. These changes should be willingly accepted for good. In the long run, however, `the benefits are clear and will be worth the effort.
We at Freyr are taking initiatives to prepare for eCTD 4.0, like
- Staying Informed: Keeping abreast of updates and guidelines related to eCTD 4.0 from Regulatory authorities such as the FDA and EMA. Attending training sessions, webinars, and conferences to understand the changes and requirements.
- Updating Systems and Software: Ensuring that company's electronic submission systems and software are compatible with eCTD 4.0 standards. Considering upgrading or implementing new tools (FREYR SUBMIT PRO) to support the updated format.
- Training Staff: Providing training to Regulatory affairs professionals, submission coordinators, and other relevant personnel on the changes introduced in eCTD 4.0. Ensure that they are familiar with the new requirements and processes.
- Reviewing and Revise Templates: Reviewing existing templates for Regulatory submissions and update them to align with eCTD 4.0 specifications. Making necessary adjustments to ensure compliance with the new standard.
- Conducting Mock Submissions: Practicing, submitting Regulatory information in the eCTD 4.0 format through mock submissions. This will help identify any issues or gaps in the process and allow for adjustments before actual submissions.
By taking these proactive steps and preparing in advance for eCTD 4.0, Freyr can ensure a smooth transition to the updated standard and maintain compliance with Regulatory requirements.
How Freyr is a differentiator?
Freyr assists Life Sciences organizations to streamline the entire Regulatory Publishing and Submissions management process. The Regulatory filing process initiates right from dossier development that includes Regulatory Submission Management and Regulatory Submission planning, tracking, Regulatory publishing, and making the final Regulatory submissions to Health Authorities (HAs) including delivery confirmation/acknowledgment for their Regulatory approvals.
As global HAs are accepting Regulatory submissions in the electronic format, the need of the hour is to deploy robust and ever-updated Regulatory publishing and submission tools to manage region-wise Regulatory submission Documents and region-specific formats. Freyr ensures error-free Regulatory submissions with the utmost quality and has proven itself for on-time Regulatory publishing and submission services for all kinds of acceptable formats such as paper, electronic submissions, eCTD, and NeeS.
Apart from deploying experienced experts to provide Regulatory publishing and submission services, Freyr offers industry-proven eCTD publishing and electronic submission software, Freyr SUBMIT PRO, to enable companies effectively meet all their specific and unique Regulatory publishing and submission services requirements for quick reviews and faster approvals of their products such as drugs, biologics, and medical devices from the Regulatory authorities.
Freyr: Global expert in Publishing and Submissions services
FREYR enables your Regulatory submissions to publish in compliance with Health Authorities across the globe for both simple and complex applications (including IND, NDA, ANDA, MAA, BLA, CTA and DMF) throughout the product lifecycle. We have resources readily available and technology for publishing eCTD, NeeS and paper formats for all types of submissions for North America, EU and APAC regions. We at Freyr can do submission planning throughout the product lifecycle. All submission services are supported by our experienced Regulatory intelligence team, whose deep knowledge of local and regional guidelines ensure the provision of compliant and efficient Regulatory publishing services. We can help streamline your end-to-end submissions management process, from dossier development to health authority interactions.
We do document level publishing and submission level publishing, Our eCTD publishing services and document level publishing expertise take the complexity out of commonly experienced problems, such as formatting and hyperlinking issues, floating sections, and error corrections. In the complex world of Regulatory publishing and submission, identifying and addressing gaps in documentation and compliance is paramount to success. At Freyr, we understand the importance of thorough gap analysis and validation to ensure that our client's submissions are error-free and meet the stringent requirements of Regulatory agencies worldwide. We conduct comprehensive gap analyses, meticulously reviewing all aspects of our clients’ Regulatory documentation to identify any discrepancies, inconsistencies, or areas of non-compliance. Whether it’s missing data, incomplete information, or formatting issues, we leave no stone unturned in our quest to ensure that our client’s submissions are of the highest quality.
Once gaps have been identified, our team works diligently to address each issue, collaborating closely with our clients to implement solutions that meet Regulatory standards and requirements. We do validate the submissions to ensure that are error-free and ready for Regulatory review. Our team uses highly recommended validators which meticulously review each submission, conducting thorough quality checks to identify and rectify any errors or discrepancies before submission. Whether it’s updating documentation, conducting additional studies, or revising processes, we leverage our expertise and industry knowledge to ensure that all gaps are effectively closed.
Compilation, publishing and submission of documents for new investigational and marketing application such as CTAs and INDs and related amendments, MAAs, NDA, ANDA and BLAs and related variations and for other health authorities. The Regulatory Filing process initiates right from dossier development that includes Regulatory Submission Management and Regulatory Submission planning, tracking, Regulatory publishing, and making the final Regulatory submissions to Health Authorities (HAs) including delivery confirmation/acknowledgment for their Regulatory approvals.
Freya Submit
Navigating the intricate world of eCTD submissions requires meticulous attention to detail and a thorough understanding of its key components. Let's delve deeper into how Using Freya Submit, Freyr Publishing Specialists facilitate the submissions for HA approvals.
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